Methods for treating rheumatoid arthritis using IL-17 antagonists

ABSTRACT

A method of treating a mammal afflicted with rheumatoid arthritis comprising administering a soluble form of IL-17 receptor is disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.10/033,522, filed Oct. 18, 2001, now allowed, which claims the benefitunder U.S.C. 119(e) of U.S. provisional application Ser. No. 60/241,230,filed Oct. 18, 2000. Which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention pertains to methods for treating certain diseases anddisorders associated with inflammatory and immunoregulatory responses.More particularly, the present invention involves treating rheumatoidarthritis by administering an IL-17 inhibitor or IL-17 antagonist, inparticular IL-17 receptor, to an individual afflicted with suchrheumatoid arthritis.

2. Description of Related Art

Cytokines are hormone-like molecules that regulate various aspects of animmune or inflammatory response. Cytokines exert their effects byspecifically binding receptors present on cells, and transducing asignal to the cells. Rouvier et al. (J. Immunol. 150:5445; 1993)reported a novel cDNA which they termed CTLA-8; cloning of the humanhomolog led to the identification of this family of molecules asInterleukin-17 (IL-17; Yao et al., Immunity 3:811; 1995). IL-17 is acytokine produced by activated T cells that stimulates the secretion ofvarious proinflammatory molecules, including tumor necrosis factor α(TNF-α), Interleukin-1 β (IL-1 β) and prostaglandin E₂ (PGE₂) frommacrophages (Jovanovic et al., J. Immunol. 160:3513; 1998).

TNF-α and IL-1 are believed to play a role in the inflammation and bonedestruction that occurs in rheumatoid arthritis (RA), albeit throughdifferent mechanisms (Joosten et al., J. Immunol. 163:5049; 1999).Moreover, elevated levels of IL-17 have been reported to occur in thesynovial fluid of RA patients, and may play a role in the bonedestruction characteristic of RA (Chabaud et al., Arthritis Rheum.42:963, 1999; Jovanovic et al., Arthritis Rheum. 43:1134, 2000).

IL-17 acts on cells by binding to a specific receptor, IL-17R, which wasisolated as described U.S. Pat. No. 6,072,033, issued Jun. 6, 2000.IL-17R is present on numerous cell types, including synoviocytes andmonocytes/macrophages. Although there are numerous agents known in theart that are used in the treatment of RA, there is a need to identifyadditional molecules that can be used to treat or ameliorate thesymptoms of this chronic inflammatory disease.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating a mammal afflictedwith a condition that relates to an inflammatory response, inparticular, rheumatoid arthritis, by administering an IL-17 antagonistthat inhibits IL-17 mediated signaling to a cell via membrane-boundIL-17 receptor. Suitable IL-17 antagonists include soluble IL-17receptor, antagonistic antibodies that specifically bind IL-17,antagonistic antibodies to IL-17 receptor and combinations thereof.

Provided herein are methods for treating medical disorders associatedwith IL-17 mediated inflammatory reactions or IL-17 mediatedimmunoregulatory reactions. The methods of the present invention includeadministering an IL-17 antagonist, or IL-1 inhibitor, that inhibitsIL-17 inflammatory or immunoregulatory signaling, to an individualafflicted with an inflammatory or immunoregulatory disease mediated byIL-17. More particularly, the present invention involves administeringan IL-17 antagonist such as IL-17 receptor, to an individual inflictedwith rheumatoid arthritis, for a period of time sufficient to induce asustained improvement in the patient's condition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for treating an individualincluding a human, who is suffering from a medical disorder that isassociated with IL-17 mediated inflammatory reactions or IL-1 mediatedimmunoregulatory reactions. For purposes of this disclosure, the terms“illness,” “disease,” “medical condition” or “abnormal condition” areused interchangeably with the term “medical disorder.”

The subject methods involve administering to the patient an IL-17antagonist or IL-17 inhibitor that is capable of reducing the effectiveamount of endogenous biologically active IL-17, by preventing thebinding of IL-17 to its receptor. Such antagonists includereceptor-binding peptide fragments of IL-17, antibodies directed againstIL-17 (antibodies that bind IL-17 and inhibit binding thereof to IL-17receptor), antibodies directed against IL-17 receptor (antibodies thatbind IL-17 receptor and inhibit receptor binding of IL-17 withoutthemselves transducing a signal via IL-17 receptor), soluble forms ofIL-17 receptor as discussed herein, molecules that bind IL-17 or IL-17receptor and inhibit the interaction thereof and polypeptides comprisingall or portions of receptors for IL-17 or modified variants thereof,including genetically-modified muteins, multimeric forms andsustained-release formulations thereof. Particular antagonists aresoluble forms of IL-17 receptor. Other particular IL-17 antagonistsencompass chimeric proteins that include portions of both an antibodymolecule and an IL-17 antagonist molecule, particularly a solubleportion of IL-17 receptor fused to an Fc. Such chimeric molecules mayform monomers, dimers or higher order multimers. Preferred methods ofthe invention utilize IL-17 receptor in a form that binds IL-17 andblocks IL-17 signal transduction, thereby interrupting theproinflammatory and immunoregulatory effects of IL-17.

The characterization, cloning and preparation of IL-17 receptor isdescribed U.S. Pat. No. 6,072,033, issued Jun. 6, 2000, incorporatedherein by reference. The amino acid sequence of the human IL-17 receptor(huIL-17 receptor) is shown in SEQ ID NO:1. The huIL-17 receptor has anN-terminal signal peptide with a predicted cleavage site between aminoacid 27 and 28. The signal peptide is followed by a 293 amino acidextracellular domain, a 21 amino acid transmembrane domain, and a 525amino acid cytoplasmic tail. Soluble forms of huIL-17 receptor that areuseful in the methods of the present invention include the extracellulardomain (residues 1-320 of SEQ ID NO:1 or residues 28-320 which excludesthe signal peptide) or a fragment of the extracellular domain that hasthe properties of antagonizing or preventing binding of IL-17 receptorto IL-17. Other forms of the IL-17 receptor that are useful in thepresent invention include muteins and variations that are at least 70%or at least 90% homologous to the native IL-17 receptor of SEQ ID NO:1and as described in U.S. Pat. No. 6,072,033.

Other derivatives of the IL-17 receptor protein and homologs thereofthat are useful in the practice of this inventive method includecovalent or aggregative conjugates of the protein or its fragments withother proteins or polypeptides, such as by synthesis in recombinantculture as N-terminal or C-terminal fusions. For example, the conjugatedpeptide may be a signal (or leader) polypeptide sequence at theN-terminal region of the protein which co-translationally orpost-transitionally directs transfer of the protein from its site ofsynthesis to its site of function inside or outside of the cell membraneor wall (e.g., the yeast a-factor leader).

Suitable forms of IL-17 inhibitors include chimeric proteins whichinclude a second polypeptide that may promote the spontaneous formationby the chimeric protein of a dimer, trimer or higher order multimer thatis capable of binding IL-17 and preventing it from binding to acell-bound receptor that promotes IL-17 signaling and inhibits orreduces the effects of inflammation and symptoms of rheumatoidarthritis. Chimeric proteins used as antagonists may be proteins thatcontain portions of an antibody molecule and a soluble IL-17 receptor.Suitable fusion proteins include a IL-17 receptor polypeptide, e.g. theextracellular domain, or an IL-17 antagonistic fragment of theextracellular domain, linked to an immunoglobulin Fc region. Fragmentsof an Fc region may also be used, as well as Fc muteins that exhibitdecreased affinity for Fc receptors. A preferred Fc region is shown inSEQ ID NO:2. Depending on the portion of the Fc region used, a fusionprotein may be expressed as a dimer, through formation of interchaindisulfide bonds. If the fusion proteins are made with both heavy andlight chains of an antibody, it is possible to form a protein oligomerwith as many as four IL-17 receptor regions.

Oligomeric forms of IL-17 inhibitors suitable for use in the presentinvention also include an IL-17 receptor, the extracellular domain of anIL-17 receptor, or an IL-17 inhibiting fragment of the extracellulardomain associated with a zipper domain, such as zipper proteinsdescribed in U.S. Pat. No. 5,716,805, the disclosure of which isincorporated by reference herein. Other Examples of zipper domains arethose found in the yeast transcription factor GCN4 and a heat-stableDNA-binding protein found in rat liver (C/EBP; Landschulz et al.,Science 243:1681, 1989), the nuclear transforming proteins, fos and jun,which preferentially form a heterodimer (O'Shea et al., Science 245:646,1989; Turner and Tjian, Science 243:1689, 1989), and the gene product ofthe murine proto-oncogene, c-myc (Landschulz et al., Science 240:1759,1988). The fusogenic proteins of several different viruses, includingparamyxovirus, coronavirus, measles virus and many retroviruses, alsopossess leucine zipper domains (Buckland and Wild, Nature 338:547, 1989;Britton, Nature 353:394, 1991, Delwart and Mosialos, AIDS Research andHuman Retroviruses 6:703, 1990). Examples of preferred zipper domainsare those of SEQ ID NO:3 and SEQ ID NO:4.

Other types of protein-based therapeutics are antibodies thatspecifically recognize one or more epitopes of IL-17, or epitopes ofconserved variants of IL-17, or peptide fragments of the IL-17polypeptide that competitively inhibit IL-17 activity. Antibodies toIL-17 can most conveniently be raised to a recombinantly produced formof the protein. Or, antibodies that specifically recognize a componentof the IL-17 receptor and that prevent signaling through the receptor byIL-17 can be used to inhibit IL-17 activity. IL-17 antagonists that areantibodies include but are not limited to polyclonal antibodies,monoclonal antibodies (mAbs), humanized or chimeric antibodies, singlechain antibodies, Fab fragments, F(ab′)₂ fragments, fragments producedby a Fab expression library, anti-idiotypic (anti-Id) antibodies, andepitope-binding fragments of any of the above. Thus, such antibodiescan, therefore, be utilized as part of inflammatory disorder treatmentmethods.

For the production of antibodies, various host animals can be immunizedby injection with the IL-17 polypeptide, truncated IL-17 polypeptides, acomponent of the IL-17 receptor (e.g., the IL-17 extracellular region),a truncated version of a component of the IL-17 receptor, and functionalequivalents and mutants thereof. Such host animals may include but arenot limited to rabbits, mice, and rats, to name but a few. Variousadjuvants may be used to increase the immunological response, dependingon the host species, including but not limited to Freund's (complete andincomplete), mineral gels such as aluminum hydroxide, surface activesubstances such as lysolecithin, pluronic polyols, polyanions, peptides,oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and potentiallyuseful human adjuvants such as BCG (bacille Calmette-Guerin) andCorynebacterium parvum. Alternatively, libraries of antibody fragmentscan be screened and used to develop human antibodies through recombinanttechniques. Such libraries are commercially available from, for example,Cambridge Antibody Technology (Melbourne, UK), and Morphosys (Munich,Del.).

Monoclonal antibodies, which are homogeneous populations of antibodiesto a particular antigen, can be obtained by any technique that providesfor the production of antibody molecules by continuous cell lines inculture. These include, but are not limited to, the hybridoma techniqueof Kohler and Milstein, (U.S. Pat. No. 4,376,110), the human B-cellhybridoma technique (Kosbor et al., 1983, Immunology Today 4:72; Cole etal., 1983, Proc. Natl. Acad. Sci. USA 80:2026-2030), and theEBV-hybridoma technique (Cole et al., 1985, Monoclonal Antibodies AndCancer Therapy, Alan R. Liss, Inc., pp. 77-96). Such antibodies may beof any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and anysubclass thereof. The hybridoma producing the mAb may be cultivated invitro or in vivo. Or, the antibody genes can be cloned and optionallyotherwise altered, and expressed in another cell line approved forrecombinant production of protein pharmaceuticals such as, for example,CHO cells.

In addition, techniques developed for the production of “chimericantibodies” (Takeda et al., 1985, Nature, 314:452-454) by splicing thegenes from a mouse antibody molecule of appropriate antigen specificitytogether with genes from a human antibody molecule of appropriatebiological activity can be used. A chimeric antibody is a molecule inwhich different portions are derived from different animal species, suchas those having a variable region derived from a porcine mAb and a humanimmunoglobulin constant region.

Preferably, for use in humans, the antibodies are human or humanized;techniques for creating such human or humanized antibodies are also wellknown and are commercially available from, for example, Protein DesignLabs, Inc. (Fremont, Calif.), Medarex Inc. (Princeton, N.J.) andAbgennix Inc. (Fremont, Calif.).

Techniques described for the production of single chain antibodies (U.S.Pat. No. 4,946,778; Bird, 1988, Science 242:423-426; Huston et al.,1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; and Ward et al., 1989,Nature 334:544-546) can also be adapted to produce single chainantibodies against IL-17 gene products and IL-17 receptor gene products.Single chain antibodies are formed by linking the heavy and light chainfragments of the Fv region via an amino acid bridge, resulting in asingle chain polypeptide.

Antibody fragments that recognize specific epitopes can be generated byknown techniques. For example, such fragments include but are notlimited to: the F(ab′)₂ fragments which can be produced by pepsindigestion of the antibody molecule and the Fab fragments which can begenerated by reducing the disulfide bridges of the (ab′)₂ fragments.Alternatively, Fab expression libraries can be constructed (Huse et al.,1989, Science, 246:1275-1281) to allow rapid and easy identification ofmonoclonal Fab fragments with the desired sThis invention additionallyprovides for the use of soluble forms of IL-17 receptor, including theextracellular domain and suitable fragments thereof in the manufactureof a medicament for the prevention or treatment of rheumatoid arthritis.This invention additionally provides for the use of DNA encoding humanIL-17 receptor, as described in U.S. Pat. No. 6,072,033, in themanufacture of soluble IL-17 receptor for use in the manufacture of amedicament for the treatment of rheumatoid arthritis.

In one preferred embodiment of the invention, sustained-release forms ofsoluble IL-17 receptor, or other IL-17 inhibitors described herein, areused. Sustained-release forms suitable for use in the disclosed methodsinclude, but are not limited to, IL-17 receptor or other IL-17inhibitor, that is encapsulated in a slowly-dissolving biocompatiblepolymer, admixed with such a polymer, and or encased in a biocompatiblesemi-permeable implant. In addition, the soluble IL-17 receptor or maybe conjugated with polyethylene glycol (pegylated) to prolong its serumhalf-life or to enhance protein delivery. Soluble forms of IL-17receptor, including monomers, fusion proteins (also called “chimericproteins), dimers, trimers or higher order multimers, are useful informulating IL-17 antagonists for treating rheumatoid arthritis.Similarly, antibodies that antagonize the IL-17/IL-17R interaction andsignaling pathway are useful antagonists for treating rheumatoidarthritis.

To treat rheumatoid arthritis, a molecule comprising an IL-17 bindingsoluble IL-17 receptor, or antibody as described herein, is administeredto the patient in an amount and for a time sufficient to induce asustained improvement in at least one indicator that reflects theseverity of the rheumatoid arthritis. An improvement is considered“sustained” if the patient exhibits, or experiences as self-assessed,the improvement on at least two occasions separated by one to fourweeks. The degree of improvement is determined based on signs orsymptoms, and may also employ questionnaires that are administered tothe patient, such as quality-of-life questionnaires.

Various indicators that reflect the extent of the patient's rheumatoidarthritis may be assessed for determining whether the amount and time ofthe treatment is sufficient. The baseline value for the chosen indicatoror indicators is established by examination of the patient, or thepatient's own self assessment, prior to administration of the first doseof the soluble IL-17 receptor, or antagonistic antibody, as describedabove. Preferably, the baseline examination is done within about 60 daysof administering the first dose.

Improvement is induced by repeatedly administering a dose of solubleIL-17 receptor or other suitable IL-17 receptor derivative, or antibody,as described herein, until the patient manifests an improvement overbaseline for the chosen indicator or indicators. The degree ofimprovement is obtained by repeatedly administering the medicament overa period of at least a month or more, e.g., for one, two, or threemonths or longer, or indefinitely.

Any efficacious route of administration may be used to therapeuticallyadminister IL-17 receptor or antibody, as described herein. If injected,a IL-17 inhibitor can be administered, for example, via intra-articular,intravenous, intramuscular, intralesional, intraperitoneal orsubcutaneous routes by bolus injection or by continuous infusion. Othersuitable means of administration include sustained release fromimplants, aerosol inhalation, eyedrops, oral preparations, includingpills, syrups, lozenges or chewing gum, and topical preparations such aslotions, gels, sprays, ointments or other suitable techniques.Administration by inhalation is particularly beneficial when treatingdiseases associated with pulmonary disorders. Alternatively, IL-17inhibitor polypeptides, such as a soluble IL-17 receptor, may beadministered by implanting cultured cells that express the protein; forexample, by implanting cells that express a soluble IL-17 receptor. Inone embodiment, the patient's own cells are induced to produce bytransfection in vivo or ex vivo with a DNA that encodes an IL-17inhibitor, and particularly soluble IL-17 receptor. This DNA can beintroduced into the patient's cells, for example, by injecting naked DNAor liposome-encapsulated DNA that encodes soluble IL-17 receptor, or byother means of transfection. When soluble IL-17 receptor is administeredin combination with one or more other biologically active compounds,these may be administered by the same or by different routes, and may beadministered simultaneously, separately or sequentially.

Soluble IL-17 receptor or other antagonists of IL-17 preferably areadministered in the form of a physiologically acceptable compositioncomprising purified recombinant protein in conjunction withphysiologically acceptable carriers, excipients or diluents. Suchcarriers are nontoxic to recipients at the dosages and concentrationsemployed. Ordinarily, preparing such compositions entails combining theIL-17 antagonist with buffers, antioxidants such as ascorbic acid, lowmolecular weight polypeptides (such as those having fewer than 10 aminoacids), proteins, amino acids, carbohydrates such as glucose, sucrose ordextrins, chelating agents such as EDTA, glutathione and otherstabilizers and excipients. Neutral buffered saline or saline mixed withconspecific serum albumin are exemplary appropriate diluents. The IL-17receptor or antagonistic antibody, preferably is formulated as alyophilizate using appropriate excipient solutions (e.g., sucrose) asdiluents. Appropriate dosages can be determined in standard dosingtrials, and may vary according to the chosen route of administration. Inaccordance with appropriate industry standards, preservatives may alsobe added, such as benzyl alcohol. The amount and frequency ofadministration will depend, of course, on such factors as the nature andseverity of the indication being treated, the desired response, the ageand condition of the patient, and so forth.

In one embodiment of the invention, the IL-17 inhibitor is administeredone time per week to treat rheumatoid arthritis, in another embodimentis administered at least two times per week, and in another embodimentis administered at least once per day. An adult patient is a person whois 18 years of age or older. If injected, the effective amount, peradult dose, ranges from 1-200 mg/m², or from 1-40 mg/m² or about 5-25mg/m². Alternatively, a flat dose may be administered, whose amount mayrange from 2-400 mg/dose, 2-100 mg/dose or from about 10-80 mg/dose. Ifthe dose is to be administered more than one time per week, an exemplarydose range is the same as the foregoing described dose ranges or lower.Preferably, the IL-17 inhibitor is administered two or more times perweek at a per dose range of 25-100 mg/dose. In one embodiment of theinvention, the various indications described below are treated byadministering a preparation acceptable for injection containing IL-17inhibitor at 80-100 mg/dose, or alternatively, containing 80 mg perdose. The dose is administered repeatedly. If a route of administrationother than injection is used, the dose is appropriately adjusted inaccord with standard medical practices. For example, if the route ofadministration is inhalation, dosing may be one to seven times per weekat dose ranges from 10 mg/dose to 50 mg per dose.

In many instances, an improvement in a patient's condition will beobtained by injecting a dose of up to about 100 mg of IL-17 inhibitorrone to three times per week over a period of at least three weeks,though treatment for longer periods may be necessary to induce thedesired degree of improvement.

For pediatric patients (age 4-17), a suitable regimen involves thesubcutaneous injection of 0.4 mg/kg to 5 mg/kg of IL-17 inhibitor,administered by subcutaneous injection one or more times per week.

The invention further includes the administration of an IL-17 inhibitorconcurrently with one or more other drugs that are administered to thesame patient, each drug being administered according to a regimensuitable for that medicament. This encompasses pre-treatment,simultaneous treatment, sequential treatment and alternating regimens.Examples of such drugs include but are not limited to analgesics,corticosteroids, antagonists of inflammatory cytokines, DMARDs,including methotrexate, and non-steroidal anti-inflammatories.Additionally, IL-17 inhibitors described herein, may be combined witheach other or combined with other molecules that reduce endogenous IL-17levels.

In one preferred embodiment of the invention, methods for treatingrheumatoid arthritis include administering soluble IL-17 receptor orother IL-17 inhibitor described herein, in combination with one or moreadditional cytokines or cytokine inhibitors. For example, an IL-17inhibitor may be administered in a composition with agents that inhibitthe interaction of inflammatory cytokines with their receptors. Suitableagents that may be utilized in combination with IL-17 inhibitors, butare not limited to, IL-1 inhibitors, such as type II IL-1 receptor,including IL-1 binding fragments of type II IL-1 receptor, disclosed inU.S. Pat. No. 5,350,683; IL-1 binding and IL-1 inhibitory fragments oftype I IL-1 receptor; IL-1 receptor antagonist, IL-1 beta convertingenzyme (ICE) inhibitors, antibodies to IL-1, including IL-1 alpha andIL-1 beta and other IL-1 family members, and therapeutics known as IL-1traps and antagonistic type I IL-1 receptor antibodies; TNF inhibitorssuch as antagonistic TNF antibodies; soluble TNF receptors p55 and p75,particularly ENBREL; IL-18 inhibitors including IL-18 binding proteindisclosed in WO 0012555; inhibitory forms of IL-18 receptors, disclosedin WO 99/37772; antagonist IL-18 antibodies, and antagonistic IL-18receptor antibodies; CD30-ligand inhibitors; and, CD4 inhibitors.

Specific IL-1 inhibitors include forms of IL-Ira described in U.S. Pat.No. 5,075,222 and modified forms and variants including those describedin U.S. Pat. No. 5,922,573, WO 91/17184, WO 92 16221, and WO 96 09323,all of which are incorporated herein by reference. IL-1 beta convertingenzyme (ICE) inhibitors include peptidyl and small molecule ICEinhibitors including those described in PCT patent applications WO91/15577; WO 93/05071; WO 93/09135; WO 93/14777 and WO 93/16710; andEuropean patent application 0 547 699. Non-peptidyl compounds includethose described in PCT patent application WO 95/26958, U.S. Pat. No.5,552,400, U.S. Pat. No. 6,121,266, Dolle et al., J. Med. Chem., 39, pp.2438-2440 (1996). Additional ICE inhibitors are described in U.S. Pat.Nos. 6,162,790, 6,204,261, 6,136,787, 6,103,711, 6,025,147, 6,008,217,5,973,111, 5,874,424, 5,847,135, 5,843,904, 5,756,466, 5,656,627,5,716,929.

Further, suitable IL-1 antagonists encompass chimeric proteins thatinclude portions of both an antibody molecule and an IL-1 antagonistmolecule. Such chimeric molecules may form monomers, dimers or higherorder multimers. Other suitable IL-1 antagonists include peptidesderived from IL-1 that are capable of binding competitively to the IL-1signaling receptor, IL-1 R type I.

Additional inhibitors used in combination with IL-17 receptor includethose that antagonize TGFβ, IFNγ, IL-6 or IL-8. The cytokine inhibitorsmay be administered as separate compositions, or together with IL-17receptor, and the cytokine inhibitors may be administered by the same ordifferent routes.

Where the compounds are used together with one or more other components,the compound and the one or more other components may be administeredsimultaneously, separately or sequentially (usually in pharmaceuticalformat).

It is understood that the response by individual patients to theaforementioned medications or combination therapies may vary, and themost efficacious combination of drugs for each patient will bedetermined by the treating physician or physicians.

The following examples are offered by way of illustration, and not byway of limitation. Those skilled in the art will recognize thatvariations of the invention embodied in the examples can be made,especially in light of the teachings of the various references citedherein, the disclosures of which are incorporated by reference herein.

EXAMPLE 1

This example describes a construct for expression of an IL-17R/Fc fusionprotein. Construction of the IL-17 receptor DNA is described in U.S.Pat. No. 6,072,033, issued Jun. 6, 2000. Briefly, a soluble form ofIL-17 receptor fused to the Fc region of human IgG1 was constructed inthe mammalian expression vector pDC409 by utilizing a 980 bp DNAfragment (nucleotides encoding the amino acid sequence of residues 1 to322 of IL-17 receptor as shown in SEQ ID NO:1) amplified from IL-17receptor cDNA in a three way ligation with a DNA fragment encoding humanIgG1 Fc (SEQ ID NO:3) and the plasmid pDC409 (described U.S. Ser. No.08/235,397).

The IL-17 receptor/Fc expression plasmids were transfected intomammalian cells (for example, CV-1/EBNA cells), and supernatantscollected. Following the collection, the IL-17 receptor/Fc fusionproteins were purified on a protein A sepharose column (Pharmacia,Uppsala, Sweden) as described below. Protein concentration wasdetermined by an enzyme-linked immunoadsorbent assay specific for theIgG Fc domain and by BCA analysis (Pharmacia); purity was confirmed bySDS-polyacrylamide gel electrophoresis analysis followed by silver stainof the gel.

EXAMPLE 2

This example describes purification of IL-17 receptor fusion proteins.IL-17 receptor/Fc fusion protein was purified by conventional methodsusing Protein A or Protein G chromatography. Approximately one liter ofculture supernatant containing IL-17 receptor/Fc fusion protein waspurified by filtering mammalian cell supernatants (e.g., in a 0.45 mfilter) and applying filtrate to a protein A/G antibody affinity column(Schleicher and Schuell, Keene, N.H.) at 4° C. at a flow rate of 80ml/hr for a 1.5 cm×12.0 cm column. The column was washed with 0.5 M NaClin PBS until free protein was not detected in the wash buffer. Finally,the column was washed with PBS. Bound fusion protein was eluted from thecolumn with 25 mM citrate buffer, pH 2.8, and brought to pH 7 with 500mM Hepes buffer, pH 9.1.

EXAMPLE 3

This example describes results obtained using IL-17 receptor in a murinemodel of rheumatoid arthritis. Mice (male DBA/1 mice five to eight weeksold) were immunized intradermally at the base of the tail with 100 μgtype II collagen (CII) in complete Freund's adjuvant (CFA). Twenty-onedays later, the mice were boosted with 200 μg CII in incomplete Freund'sadjuvant (IFA) intradermally at the base of the tail. Signs of clinicalarthritis begin to appear in the mice three to five days after thebooster.

Mice were evaluated for signs of clinical score and disease incidencethree times weekly, beginning at the time of the booster. Diseaseseverity was evaluated using an established arthritis index system. Eachpaw was assigned a clinical score based on the index. Paw scores foreach animal were combined to determine a total cumulative score. Thearthritis index used was: 0=normal appearance; 1=erythema/edema in 1-2digits; 2=erythema/edema in more than two digits, or mild swelling inankle/wrist joint; 3=erythema/edema in entire paw; 4=massiveerythema/edema of entire paw extending into proximal joints, ankylosis,loss of function.

At the time of the booster, mice (15-20 mice per group) were injectedintraperitoneally with either 150 μg rat IgG, 1 μg TNF receptor/Fc, 150μg IL-17 receptor/Fc as prepared in Examples 1 and 2, or a combinationof 1 μg TNF receptor/Fc and 150 μg IL-17 receptor/Fc. The treatmentregimen was repeated daily for fourteen days. The mice were evaluatedfor clinical score and disease incidence three times weekly. The averagefinal score for each group is shown in Table 1. TABLE 1 Decrease ofArthritis Symptoms in Mice Given TNF receptor/Fc and/or IL-17receptor/Fc Group: Treatment: Average Final Score: Group 1 Rat IgG 8.4Group 2 TNF receptor/Fc 5.7 Group 3 IL-17 receptor/Fc 5.1 Group 4 TNFreceptor/Fc plus IL-17 receptor/Fc 1.7

A second set of experiment using substantially the same parameters wascarried out. The average final score for each group is shown in Table 2:TABLE 2 Decrease of Arthritis Symptoms in Mice Given TNF receptor/Fc andIL-17 receptor/Fc, Group: Treatment: Average Final Score: Group 1 RatIgG 9.2 Group 2 TNF receptor/Fc 5.9 Group 3 IL-17 receptor/Fc 3.9 Group4 TNF receptor/Fc plus IL-17 receptor/Fc 5.0

These results indicate that IL-17 receptor ameliorates the symptoms ofarthritis in an animal model of rheumatoid arthritis. Moreover, IL-17receptor may be used in combination with TNF receptor (or otherinhibitors of inflammation) to reduce the severity of clinicalarthritis.

1. A method of treating an individual afflicted with rheumatoidarthritis comprising administering to the individual IL-17 receptor. 2.A method of treating an individual afflicted with rheumatoid arthritiscomprising administering to the individual a therapeutic comprising apolypeptide selected from the group consisting of the extracellulardomain of human IL-17 receptor and a fragment of the extracellulardomain of human IL-17 receptor, wherein the fragment inhibits thebinding of IL-17 receptor and IL-17.
 3. A method of treating anindividual afflicted with rheumatoid arthritis, the method comprisingadministering to the individual a therapeutic comprising a polypeptideselected from the group consisting of: (a) a polypeptide having aminoacids 33 through 322 of SEQ ID NO:1; (b) a polypeptide that is at leastabout 70% identical to the polypeptide of (a) and that binds IL-17; and(c) fragments of the proteins of (a) or (b), that bind IL-17.
 4. Themethod of claim 2, wherein the therapeutic is a chimeric fusion proteinthat further comprises an immunoglobulin Fc.
 5. The method according toclaim 2, further comprising administering, one or more therapeuticsselected from the group consisting of a TNF antagonist and an IL-1antagonist.
 6. The method of claim 5, wherein the IL-1 antagonist isselected from the group consisting of soluble IL-1 receptor type II,IL-IR type I antibody, IL-1 receptor antagonist, and fusion proteincomprising soluble IL-1 receptor type I, and soluble IL-1 receptoraccessory protein.
 7. The method of claim 5 wherein the TNF antagonistis selected from the group consisting of TNF antibodies, soluble TNFreceptor p75, and soluble TNF receptor p55.